This application proposes an integrated program of work on lung cancer based on the research opportunity afforded by the high risk of former uranium miners in New Mexico and Colorado for this malignancy. The program includes investigation of quantitative risks of lung cancer in relation to exposure to radon progeny, of determinants of susceptibility, and of molecular and cellular markers of carcinogenesis. The need for research in these areas is evident. Lung cancer remains a pressing worldwide public health problem and indoor radon is now recognized as the second leading cause of lung cancer in the United States. Techniques of molecular and cellular biology provide new markers for describing the longitudinal process of carcinogenesis and for screening. Uranium miners have a markedly increased excess risk of lung cancer that is determined by exposure to radon progeny and smoking. The states of New Mexico, Colorado, Arizona, and Utah have a large number of former miners who are now at high risk for lung cancer because of these exposures. We have already investigated the risks of lung cancer in a cohort of 3,500 New Mexico uranium miners and in Navajo uranium miners. The program described in this application extends these studies following a molecular epidemiology model. It draws on resources in epidemiology at the New Mexico Tumor Registry in the Cancer Research and Treatment Center at the University of New Mexico and in molecular and cellular biology at the Lovelace Inhalation Toxicology Research Institute. The applicant will participate as a member of the interdisciplinary research team that is implementing a broad program on the molecular epidemiology of lung cancer in uranium miners. During the three years of this award, he will use the initial data from the project and data from other resources on uranium miners to accomplish the following: l. Using a newly developed cohort of high risk uranium miners, a) determine the prevalence on enrollment of cellular and molecular changes in exfoliated respiratory cells and define their relationship to radon exposure and smoking; and b) describe the temporal pattern of cellular and molecular events in respiratory carcinogenesis as the cohort is followed longitudinally; and c) Quantify the lung cancer risk associated with cellular and molecular markers that occur with high prevalence. 2. Using the New Mexico Tumor Registry database on incident cancers in Navajo males, 1969-1993. a) determine the magnitude and temporal trends in uranium- mining associated risk of lung cancer; b) describe the distribution of histologic types in Navajo males and a cohort of New Mexico uranium miners; 3. Using the cohort of underground miners screened through a state wide screening program operated by the Miners' Colfax Medical Center, a) assess pulmonary function as a marker of lung cancer susceptibility; and b) determine lung cancer risk associated with the presence of silicosis.